effects of glucagon like peptide-1(glp-1) and liraglutide on brain satiety and reward circuits and feeding behavior in diabetes

Conditions: Obesity; Type 2 Diabetes

Summary: the aim of this study is to investigate if endogenous glucagon like peptide -1 (glp-1) has an effect on brain satiety and reward systems and if there are alterations in obese patients with type 2 diabetes (t2dm). secondly, the aim is to investigate whether treatment with a glp-1 analog, liraglutide, restores these signals in obese patients with type 2 diabetes. finally, also the endogenous glp-1 effects will be investigated in obese individuals before and after gastric bypass surgery on brain satiety and reward systems.

first aim will be addressed in a cross-sectional randomized study. 20 healthy, lean and 20 obese individuals with type 2 diabetes (t2dm) will be exposed to food cues and with concomitant infusion of glucagon like peptide-1 (glp-1) receptor antagonist or saline, to assess the involvement of endogenous glp-1, secreted in response to a meal. measurements activation of cns circuits involved in satiety and reward will be performed using blood oxygen level-dependent (bold) functional magnetic resonance imaging (fmri). the second aim will be addressed in cross-over randomized-controlled trial (rct) in the t2dm patients only. patients will be randomly assigned liraglutide vs insulin glargine treatment, during a treatment period of 12 weeks each with a 12-week washout period in between. the investigators will perform the same fmri protocol. the third aim will be addressed in a study with obese individuals who are scheduled for a gastric bypass surgery. the same protocol as for the first aim will be performed and this will be before and after the surgery in the same individuals.

Eligibility criteria:
inclusion criteria: * for the healthy, lean individuals: * age 18-65 years * women: post menopausal (excluding possible menstruation cycle effects) * body-mass index (bmi) of \<25 kg/m2, * stable bodyweight (\<5% reported change during the previous 3 months). * normal fasting and 2h post load glucose as ascertained during a 75-g oral glucose tolerance test (ogtt) (34) * right handed for the obese t2dm individuals: * age 18-65 years * women: post menopausal (excluding possible menstruation cycle effects) * bmi 25-40 kg/m2 * stable bodyweight (\<5% reported change during the previous 3 months). * diagnosed with t2dm \> 3 months prior to screening * hba1c 6.5-8.5% * treatment with metformin at a stable dose for at least 3 months. * right handed for the obese individuals scheduled for gastric bypass surgery: * age 18-65 years * women: preferably post menopausal (excluding possible menstruation cycle effects) * body-mass index (bmi) of \>30 kg/m2, * stable bodyweight (\<5% reported change during the previous 1 months). * normal or impaired fasting and 2h post load glucose as ascertained during a 75-g oral glucose tolerance test (ogtt) (defined as glucose fasting \< 7.1 mmol/l and after ogtt t=120min \< 11.0 mmol/l) (39) * right handed exclusion criteria: * glp-1 based therapies, thiazolidinediones, sulphonylurea or insulin within 3 months before screening * weight-lowering agents within 3 months before screening. * congestive heart failure (nyha ii-iv) * chronic renal failure (glomerular filtration rate \< 60 ml/min/1.73m2 per modification of diet in renal disease (mdrd)) * liver disease * history of gastrointestinal disorders (including gastropareses, pancreatitis and cholelithiasis) * neurological illness * malignancy * other type of bariatric surgery (redo-gbp, sleeve, distal gbp, adj banding, scopinaro) * history of major heart disease * history of major renal disease * pregnancy or breast feeding * implantable devices * substance abuse * addiction * contra-indication for mri, such as claustrophobia or pacemaker * any psychiatric illness; including eating disorders and depression * chronic use of centrally acting agents or glucocorticoids within 2 weeks immediately prior to screening. * use of cytostatic or immune modulatory agents * history or known allergy for acetaminophen. * history of allergy for insulin analog * history of allergy for liraglutide * participation in other studies * individuals who have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry * individuals who are investigator site personnel, directly affiliated with the study, or are immediate family